Formulation of Compounds by SAR Analysis for HIV‐1 Capsid Core Inhibition

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In the human immunodeficiency virus replication life cycle, thousands of the viral Gag polyprotein associate at the cell membrane. The virus buds to form a non‐infectious virion. Gag is then cleaved by protease. Capsid protein is released and assembles into the capsid core, creating an infectious virus. The capsid protein is an attractive inhibition site because its formation of the capsid core is crucial for viral infectivity. A compound, CAP‐1, has been identified that binds to the N‐terminal domain of the capsid protein (CAN) and inhibits capsid formation in vitro and in vivo, but the dissociation constant (Kd) is not within an acceptable range for clinical use. We have been testing new compounds for affinity with a Kd in the nanomolar range. NMR HSQC titrations have been used to calculate the Kd. The computer program, PyMOL, has been used to give a visual representation of the binding pocket conformation of the compounds bound to the capsid protein. A correlation has been found between the amount of unoccupied space within the pocket and the Kd. Using this information, several compounds’ pocket conformations and Kd values were screened. Taking a structure activity relationship (SAR) approach, four potential inhibitors were formulated. All four targets are currently in the synthesis phase. The results of the future NMR HSQC titrations will provide the data needed for the next steps in the drug design.